Environmental and genetic perturbations reveal different networks of metabolic regulation.

Abstract

Progress in systems biology depends on accurate descriptions of biological networks. Connections in a regulatory network are identified as correlations of gene expression across a set of environmental or genetic perturbations. To use this information to predict system behavior, we must test how the nature of perturbations affects topologies of networks they reveal. To probe this question, we focused on metabolism of Drosophila melanogaster. Our source of perturbations is a set of crosses among 92 wild-derived lines from five populations, replicated in a manner permitting separate assessment of the effects of genetic variation and environmental fluctuation. We directly assayed activities of enzymes and levels of metabolites. Using a multivariate Bayesian model, we estimated covariance among metabolic parameters and built fine-grained probabilistic models of network topology. The environmental and genetic co-regulation networks are substantially the same among five populations. However, genetic and environmental perturbations reveal qualitative differences in metabolic regulation, suggesting that environmental shifts, such as diet modifications, produce different systemic effects than genetic changes, even if the primary targets are the same.

Data structure and heritability estimates. (A) The diallel crossing scheme. Male parents are listed top to bottom, female parents—left to right. Black boxes indicate the crosses we performed. Gray boxes mark the ‘selfed' inbred lines. (B) A depiction of the data structure showing the replication scheme and nesting of variables. (C) Narrow-sense heritability (h2) estimates for all parameters in males and females. For each estimate, the whiskers indicate the 95% credible interval, the box—the inter-quartile range, and the thick black line—the median of the samples from the posterior distribution. The data are arranged in the order of decreasing sex-averaged h2 separately for physiological variables and enzymes.

Correlation network structure. (A) The genetic correlation network estimated from male data. Gray ovals represent the variables and the lines depict correlations among them. The color of each line reflects the median posterior value of the correlation coefficient. The color distribution is described by the bar to the right. For clarity, only correlations with absolute values >0.1 are depicted. (B) The environmental correlation network in males. This panel is organized the same as (A), with the same color scheme. Differences in node arrangement reflect disparities in network structure. (C) Posterior probabilities of a given correlation being present in both the genetic and environmental matrices, and retaining the same sign. The color of each bar reflects the absolute value of the genetic correlation; the distribution of colors is depicted in (D). The individual correlations are arranged along the X axis. This arrangement is identical in all figures, row by row of the upper triangle of the correlation matrices as represented in . The horizontal gray bar reflects the range of expected values for two randomly permuted matrices. (D) Posterior probabilities that a given correlation is present in both correlation matrices and has switched sign. The plot is arranged as (C).

Degree distributions of the genetic and environmental correlation networks. Degree distributions for the genetic correlation network are on the left and the environmental ones on the right. The top two panels depict the sum of positive and negative correlations, the middle panels, only negative correlations, and the bottoms panels, only positive correlations. The posterior distributions are shown as in . For each parameter, the value of degree expected under the assumption of a uniform degree distribution (see Materials and methods for details) is subtracted from the measured value and the difference plotted on the Y axis. Enzymes and physiological variables are sorted separately in the descending order of the posterior most likely value of total degree.

Sex differences in enzyme levels and correlation network structure. (A) Sex differences in enzyme levels (among-population means), standardized by male values. (B) Across-sex correlations for each variable. Correlations were calculated using breeding values for each line. (C, D) Posterior probabilities of a given genetic correlation being present and retaining (C) or switching (D) sign between sexes. The plotting arrangements are the same as those in . (E, F) The same as (C) and (D), but for environmental correlations.